Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by phospholipase A2 inhibitors and lipoxygenase inhibitor.
Application of 12-O-tetradecanoylphorbol-13-acetate (TPA; 20 nmol/mouse), a tumor-promoting agent, to mouse skin results in an induction of epidermal ornithine decarboxylase (ODC; EC 4.1.1.17). Induction of ODC by TPA was inhibited by treatment of skin with indomethacin (1.12 mumol/mouse), a cyclooxygenase inhibitor, and the ODC activity suppressed by indomethacin was completely restored by concurrent application of prostaglandin E2 (PGE2) (140 nmol/mouse) as described first by Verma et al. (Cancer Res., 40: 308-315, 1980). Treatment of mice with tetracaine (20 and 100 mumol/mouse), a nonspecific phospholipase A2 inhibitor, inhibited the induction of ODC by TPA. More specific phospholipase A2 inhibitors, mepacrine (20 mumol/mouse) and p-bromophenacyl bromide (10 mumol/mouse), also inhibited the ODC induction. The TPA-induced ODC inhibited by mepacrine was not restored by the treatment of mice with PGE2. TPA-induced ODC inhibited by either mepacrine or p-bromophenacyl bromide was partially but significantly restored by treatment with arachidonic acid (1 to 40 mumol/mouse). Neither PGE2 nor arachidonic acid alone could induce the epidermal ODC. Treatment of mice with nordihydroguaiaretic acid (10 to 90 mumol/mouse), a lipoxygenase inhibitor, also inhibited the induction of ODC by TPA. These results strongly indicate that the stimulation of phospholipase A2 activity is a crucial process in inducing mouse epidermal ODC by TPA and not only cyclooxygenase product (i.e., PGE2) but also lipoxygenase product(s) are involved in the mechanism of ODC induction. Our present data also suggest that the above arachidonate metabolites are essential but not sufficient factors for the TPA-stimulated induction of ODC.
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology; D015232:Dinoprostone; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D010704:Phorbols / Q000494:pharmacology*; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011458:Prostaglandins E / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D012867:Skin / Q000201:enzymology*; D013748:Tetracaine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000975:Antioxidants; D001095:Arachidonic Acids; D002396:Catechols; D016859:Lipoxygenase Inhibitors; D010704:Phorbols; D011458:Prostaglandins E; D013748:Tetracaine; D016718:Arachidonic Acid; D009637:Masoprocol; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D002262:Carboxy-Lyases; D009955:Ornithine Decarboxylase; D011796:Quinacrine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin